Cigarette smoking continues to be a major cause of cardiovascular disease (CVD). In contrast, the cardiovascular risks of other tobacco products in common use (smokeless tobacco) and new tobacco products (e-cigarettes) are not adequately understood. The FDA will need information about the cardiovascular safety of these products to inform their regulatory decisions. While long-term clinical outcome studies that investigate the cardiovascular risks of tobacco products would be optimal, they take too long to provide the data that the FDA needs now. Disturbances in the function of vascular endothelium (the lining of arteries, which plays an important role in regulating vascular function), in the activation ofthe autonomic nervous system and increased inflammation, oxidative stress and propensity to thrombosis (clotting) are key mechanisms in the progression of CVD and provide useful and validated biomarkers of CVD risk. These biomarkers form the basis for our model to assess the CVD risks of tobacco product use and secondhand smoke exposure. We will conduct controlled, short-term exposures of human subjects to test products that provide a wide range of nicotine, particle and other cardiovascular toxin concentrations to determine how these components associated with tobacco use adversely affect cardiovascular risk. Specifically, we will 1) determine the relative contributions of nicotine and combustion products to the cardiovascular risk of active cigarette smoking; 2) determine which cardiovascular risk biomarkers are affected by exposure to low concentrations of secondhand smoke; 3) determine the cardiovascular risk of smokeless tobacco use; and 4) determine the cardiovascular risk of electronic cigarettes and the respective contributions of nicotine and electronic cigarette vapor. By quantifying and comparing the immediate effects of 4 different kinds of tobacco products on the cardiovascular system. Project 5 will validate a sensitive and practical panel of physiological and molecular biomarkers that predict cardiovascular disease and will be of great use in premarket human testing of tobacco products. C RELEVANCE (See instructions): Our research will provide information as to how individual key components of tobacco and nicotine delivery products, i.e. nicotine, particulate matter, and other cardiovascular toxins, affect cardiovascular risk and if smokeless tobacco and e-cigarettes pose cardiovascular risks. Ultimately, our biomarker model will serve as a cardiovascular safety screen for the FDA in its oversight of conventional, new, and emerging tobacco products.